Recent studies in this lab have identified c-Cbl as a key regulator of whole body energy expenditure and adiposity in mice. Ablation of c-Cbl in mice results in a desirable phenotype of reduced adiposity, increased lean body mass, small adipocytes, and increased energy expenditure despite hyperphagia. These mice illustrate a role for c-Cbl in an unknown facet of fuel metabolism that is integrally linked to body weight regulation. The majority of these metabolic changes occur in muscle and fat tissue, therefore the specific aims for this proposal are to 1) identify the tissue type that drives the c-Cbl -/- phenotype and 2) determine the molecular mechanism by which c-Cbl ablation results in increased fatty acid oxidation and reduced adiposity. Dissecting the c-Cbl -/- phenotype will illustrate the role of this protein in the molecular control of energy expenditure and have therapeutic applications in diabetes and obesity. The exciting aspect of these studies is that the molecular control of energy expenditure in mammals is a newly evolving field and the precise wiring diagram for this pathway has yet to be established. This study will identify novel inroads into this pathway and may pave the way for our understanding of mitochondrial energy expenditure.